Different Effects of Maternal Low-Isoflavone Soy Protein and Genistein Consumption on Hepatic Lipid Metabolism of 21-Day-Old Male Rat Offspring.

Amino acid composition and isoflavone are alleged contributors to the beneficial effects of soy protein isolate (SPI) on lipid metabolism. Therefore, we investigated the contributing component(s) of SPI in a maternal diet to the regulation of lipid metabolism in offspring. We also determined serum parameters in dams to investigate specific maternal cues that might be responsible for this regulation. Female rats were fed either a casein (CAS), a low-isoflavone SPI, or a casein plus genistein (GEN, 250 mg/kg) diet for two weeks before mating, as well as during pregnancy and lactation. Male offspring (CAS, SPI and GEN groups) were studied 21 days after birth. The SPI group had lower serum triglyceride levels than the other groups. Serum cholesterol was reduced in both the SPI and GEN groups compared with the CAS group. Expressions of target genes of peroxisome proliferator-activated receptor α were altered in the SPI group. Serum aromatic amino acid levels in dams were associated with serum triglyceride in offspring. In conclusion, the maternal consumption of a low-isoflavone SPI diet or a casein diet containing genistein has different effects on the lipid metabolism of their offspring; however, more profound effects were observed in the SPI group. Therefore, the altered lipid metabolism of offspring may be attributed to amino acid composition in maternal dietary protein sources

Can local policies on biosimilars optimize the use of freed resources – experiences from Italy

There is an increasing need to prescribe biosimilars to fund new medicines and increasing medicine volumes. Bertolani and Jommi document successful measures introduced regionally in Italy

Pharmaceutical policy, impact and health outcomes

Pharmaceutical policy is essential given increasing expenditure on medicines and only finite resources, with global expenditure on medicines estimated to reach US$1.5 trillion by the end of 2023 (1). This represents an annual compounded growth rate of 3–6$237 billion by 2024, and continue growing (4). This increase is driven by the increasing prevalence rates of patients with cancer alongside the increasing costs of new oncology medicines, with requested prices per life year gained for new oncology medicines rising four-fold or more during the past years after adjusting for inflation (4). This increase is exacerbated by the emotive nature of the disease area (6). These growth rates though are unsustainable leading to greater scrutiny over the cost and value of new oncology medicines, which will continue (

Drug pricing in South Korea

Background: Between 2000 and 2013, spending on medicines in Korea increased by 275.3%. In order to curb this trend, several pricing policies and measures were introduced. Objectives: This study reviews these policies and their implications. Methods: Review of pricing regulations as well as a literature review. Results: New medicines must now undergo both a reimbursement assessment and price negotiations. The reimbursement of new medicines is based on their cost-effectiveness. The prices of new medicines are subsequently fixed through negotiations between the payer, the National Health Insurance Service, and the relevant manufacturer. Generic drugs are automatically priced via a new standard methodology. Re-pricing mechanisms were complicated and now redundant. Conclusions: Simple and efficient measures rather than complex and inefficient measures are needed to maintain the value for money principle for new medicines as well as achieve financial efficiency through price competition among multiple s sourced drugs, building on the experiences in other countries

The impact of South Korea’s new drug-pricing policy on market competition among off-patent drugs

A new pricing policy was introduced in Korea in April 2012 with the aim of strengthening competition among off-patent drugs by eliminating price gaps between originators and generics. Examine the effect of newly implemented pricing policy. Retrospectively examining the effects through extracting from the National Health Insurance claims data a 30-month panel dataset (January 2011 - June 2013) containing consumption data in four major therapeutic classes (antihypertensives, lipid-lowering drugs, antiulcerants and antidepressants). Proxies for market competition were examined before and after the policy. The new pricing policy didn’t enhance competition among off-patent drugs. In fact, price dispersion significantly decreased as opposed to the expected change. Originator-to-generic utilization increased to 6.12 times (p=0.000) after the new policy. The new pricing policy made no impact on competition among off-patent drugs. Competition in the off-patent market cannot be enhanced unless both supply and demand-side measures are coordinated

Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS), which is one of the most common HIV-associated neoplasms. The endothelium is the thin layer of squamous cells where vascular blood endothelial cells (BECs) line the interior surface of blood vessels and lymphatic endothelial cells (LECs) are in direct contact with lymphatic vessels. The KS lesions contain a prominent compartment of neoplastic spindle morphology cells that are closely related to LECs. Furthermore, while KSHV can infect both LECs and BECs in vitro, its infection activates genetic programming related to lymphatic endothelial cell fate, suggesting that lymphangiogenic pathways are involved in KSHV infection and malignancy. Here, we report for the first time that viral interferon regulatory factor 3 (vIRF3) is readily detected in over 40% of KS lesions and that vIRF3 functions as a proangiogenic factor, inducing hypersprouting formation and abnormal growth in a LEC-specific manner. Mass spectrometry analysis revealed that vIRF3 interacted with histone deacetylase 5 (HDAC5), which is a signal-responsive regulator for vascular homeostasis. This interaction blocked the phosphorylation-dependent cytosolic translocation of HDAC5 and ultimately altered global gene expression in LECs but not in BECs. Consequently, vIRF3 robustly induced spindle morphology and hypersprouting formation of LECs but not BECs. Finally, KSHV infection led to the hypersprouting formation of LECs, whereas infection with a ΔvIRF3 mutant did not do so. Collectively, our data indicate that vIRF3 alters global gene expression and induces a hypersprouting formation in an HDAC5-binding-dependent and LEC-specific manner, ultimately contributing to KSHV-associated pathogenesis.IMPORTANCE Several lines of evidences indicate that KSHV infection of LECs induces pathological lymphangiogenesis and that the results resemble KS-like spindle morphology. However, the underlying molecular mechanism remains unclear. Here, we demonstrated that KSHV vIRF3 is readily detected in over 40% of various KS lesions and functions as a potent prolymphangiogenic factor by blocking the phosphorylation-dependent cytosolic translocation of HDAC5, which in turn modulates global gene expression in LECs. Consequently, vIRF3-HDAC5 interaction contributes to virus-induced lymphangiogenesis. The results of this study suggest that KSHV vIRF3 plays a crucial role in KSHV-induced malignancy

Leucine supplementation in maternal high-fat diet alleviated adiposity and glucose intolerance of adult mice offspring fed a postweaning high-fat diet

Background Combined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated. Methods Female mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring. Results HFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. ThemRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho β, and its downstream targets, proliferator‐activated receptor‐γ co‐activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring. Conclusions Leucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.This work was supported by the National Research Foundation of Korea grant funded by the Ministry of Science, ICT and Future Planning (No. 2014R1A1A3052400)

Respiratory Syncytial Virus-Like Nanoparticle Vaccination Induces Long-Term Protection Without Pulmonary Disease by Modulating Cytokines and T-cells Partially Through Alveolar Macrophages

The mechanisms of protection against respiratory syncytial virus (RSV) are poorly understood. Virus-like nanoparticles expressing RSV glycoproteins (eg, a combination of fusion and glycoprotein virus-like nanoparticles [FG VLPs]) have been suggested to be a promising RSV vaccine candidate. To understand the roles of alveolar macrophages (AMs) in inducing long-term protection, mice that were 12 months earlier vaccinated with formalin-inactivated RSV (FI-RSV) or FG VLPs were treated with clodronate liposome prior to RSV infection. FI-RSV immune mice with clodronate liposome treatment showed increases in eosinophils, plasmacytoid dendritic cells, interleukin (IL)-4+ T-cell infiltration, proinflammatory cytokines, chemokines, and, in particular, mucus production upon RSV infection. In contrast to FI-RSV immune mice with severe pulmonary histopathology, FG VLP immune mice showed no overt sign of histopathology and significantly lower levels of eosinophils, T-cell infiltration, and inflammatory cytokines, but higher levels of interferon-γ, which are correlated with protection against RSV disease. FG VLP immune mice with depletion of AMs showed increases in inflammatory cytokines and chemokines, as well as eosinophils. The results in this study suggest that FG nanoparticle vaccination induces long-term protection against RSV and that AMs play a role in the RSV protection by modulating eosinophilia, mucus production, inflammatory cytokines, and T-cell infiltration

Availability and Affordability of Drugs With a Conditional Approval by the European Medicines Agency; Comparison of Korea With Other Countries and the Implications

Introduction: There have been concerns with the availability and affordability of EMA’s recently approved medicines with a conditional approval in Korea. This needs to be addressed to provide future guidance to the authorities in Korea. Objective: Compare the availability and affordability of medicines with a conditional approval by the European Medicine Agency (EMA) among 12 countries (US, UK, France, Germany, Switzerland, Italy, Japan, Canada, Taiwan, Australia, New Zealand and Korea) in light of access to medicine concerns in Korea. Methods: 13 medicines were selected and compared in terms of their availability and affordability across 12 countries. Approval rate for the selected medicines and time lag to approval on the basis of EMA’s approval dates were calculated. Reimbursement status and prices were compared as proxies of affordability. Results: The average approval rate was 31.9% for the selected medicines for all countries outside the EU countries. The highest rate was in US (69.2%) followed by Korea and Switzerland (46.5%). An average of 238days was taken among the countries for approval. The US (Median -355 days) was the country where the medicines were most rapidly approved. Korea (152 days) ranked the fifth most rapidly approving country. An average listing or reimbursement rate for all countries was 54.1%. The US ranked 100% for the listing of their approved medicines followed by Germany (92.3%). Korea (66.7%) ranked eighth. Price dispersion ranged from 1.1 to 2.8. Korean prices of the selected medicines were found to be neither high nor low. Conclusions: Korea was found to be a country where marketing authorization for more medicines tended to be made and subsequent reimbursement and pricing were not rigid even generous compared to other Asian-pacific countries. Korean drug benefit policies for listing and pricing did not appear to hinder access to medicines even with a conditional approval in comparison with others